Caffey Disease: an Unlikely Collagenopathy

Caffey disease: an unlikely collagenopathy

Francis H. Glorieux

J Clin Invest. 2005;115(5):1142-1144. https://doi.org/10.1172/JCI25148.

Commentary

Infantile cortical hyperostosis (also known as Caffey disease) is characterized by hyperirritability, acute inflammation of soft tissues, and profound alterations of the shape and structure of the underlying bones, particularly the long bones, mandible, clavicles, or ribs. In this issue of the JCI, Gensure et al. undertook fine mapping of the genetic locus for this disease in a large kindred of individuals with the autosomal dominant form of the condition. The authors found a novel missense mutation in COL1A1, the gene encoding the α1 chain of type I collagen, in all affected individuals in 3 discrete pedigrees. This is a surprising finding, as all other reported mutations affecting the synthesis of type I collagen lead to conditions such as osteogenesis imperfecta and Ehlers-Danlos syndrome, in which quantitative or qualitative defects in type I collagen synthesis give rise to bone fragility and/or connective tissue hyperextensibility. The deleterious effect of the mutation on collagen fibril morphology is demonstrated; however, the precise functional link between the reported missense mutation and the localized inflammation and hyperostosis seen in Caffey disease awaits future studies.

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apolipoprotein B-100 in NIDDM. Diabetologia. 120:1183–1192. 17. Schattenberg, J.M., Wang, Y., Singh, R., Rigoli, 38:959–967. 16. Powell, E.E., et al. 1990. The natural history of R.M., and Czaja, M.J. 2005. Hepatocyte CYP2E1 15. Sanyal, A.J., et al. 2001. Nonalcoholic steato- nonalcoholic steatohepatitis: a follow-up study of overexpression and steatohepatitis lead to hepatitis: association of insulin resistance and forty-two patients for up to 21 years. Hepatology. impaired hepatic insulin signaling. J. Biol. Chem. mitochondrial abnormalities. Gastroenterology. 11:74–80. 280:9887–9894. Caffey disease: an unlikely collagenopathy Francis H. Glorieux

Departments of Surgery, Pediatrics, and Human Genetics, McGill University, and Genetics Unit, Shriners Hospital for Children, Montréal, Quebec, Canada.

Infantile cortical hyperostosis (also known as Caffey disease) is character- Bone lesions ized by hyperirritability, acute inflammation of soft tissues, and profound The radiographic features of ICH evolve alterations of the shape and structure of the underlying bones, particularly in stages. Hyperostoses develop on the the long bones, mandible, clavicles, or ribs. In this issue of the JCI, Gensure outer cortical surface, expand, and then et al. undertook fine mapping of the genetic locus for this disease in a large remodel by resorption either at the exter- kindred of individuals with the autosomal dominant form of the condition. nal surface or at the endocortical surface. The authors found a novel missense mutation in COL1A1, the gene encod- In the latter case, there is an expansion of ing the α1 chain of type I collagen, in all affected individuals in 3 discrete the medullary cavity and the cortex is thin pedigrees (see the related article beginning on page 1250). This is a surpris- (Figure 2B). Epiphyses and metaphyses are ing finding, as all other reported mutations affecting the synthesis of type I typically not involved. Tubular bones may collagen lead to conditions such as osteogenesis imperfecta and Ehlers-Dan- be grossly deformed (Figure 1), with bony los syndrome, in which quantitative or qualitative defects in type I collagen bridges sometimes appearing between synthesis give rise to bone fragility and/or connective tissue hyperextensi- adjacent bones (forearm, ribs). The histol- bility. The deleterious effect of the mutation on collagen fibril morphology ogy of the bone lesions has been described is demonstrated; however, the precise functional link between the reported in detail (3). Such lesions include not only missense mutation and the localized inflammation and hyperostosis seen in subperiosteal new lamellar bone forma- Caffey disease awaits future studies. tion but also evidence of local inflammation. Early on, foci of acute inflammation Infantile cortical hyperostosis (ICH) note that this phase of acute inflamma- are confined in the periosteum; they then — also referred to as Caffey or Caffey-Sil- tion precedes the abnormal thickening of disrupt the periosteal envelope to blend verman disease — was recognized in 1945 cortical bone (hyperostosis) that gives its with contiguous tissues (fasciae, muscle, by Caffey and Silverman (1). The condi- name to the disease. It also subsides long and tendon). In the subacute phase, the tion, later shown to be transmitted as an before the hyperostosis resolves. Some- periosteum reestablishes itself as an entity autosomal dominant trait with incom- times lesions recur suddenly in their orig- with a sheet of fibrous tissue under which plete penetrance, becomes clinically evi- inal sites or in new sites, either during or new subperiosteal bone is formed. In the dent before 5–7 months of life, and the after the subsidence of the swellings that late remodeling stage, signs of inflam- average age at onset is around 9 weeks. appeared at the onset of the disease. This mation disappear, and excess peripheral The initial symptom is general hyperirri- uneven protracted clinical course with bone is removed. tability, with fever and anorexia, quickly unpredictable remissions and relapses is Based on these facts, discussion of the followed by painful, firm soft-tissue one of the most characteristic features of pathophysiology of ICH naturally turns swelling, particularly in the face (cheeks the condition (2). toward a mechanism likely to induce and jaws), the scapular region, and upper and lower limbs. It is usually self-limited, with severe symptoms lasting from 2–3 weeks to 2–3 months. The pattern of distribution of the lesions varies from patient to patient and can be symmetri- cal (Figure 1). Swelling also involves underlying muscle. It is important to

Nonstandard abbreviations used: COL1A1, gene encoding the α1 chain of type I collagen; EDS, Ehlers- Danlos syndrome; ICH, infantile cortical hyperostosis; PGE, prostaglandin E. Conflict of interest: The author has declared that no Figure 1 conflict of interest exists. A 6-month-old girl with typical clinical findings of Caffey disease, which appeared at age 7 Citation for this article: J. Clin. Invest. 115:1142–1144 weeks. The painful swelling of soft tissue around the legs (A) is matched by severe involvement (2005). doi:10.1172/JCI200525148. of the tibia and fibula bilaterally (x-radiography, B). Femurs are strikingly unaffected.

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Figure 2 Schematic illustrating normal and exuberant bone formation. (A) Representation of a growing bone. Growth in length is achieved by endochondral bone formation adding cancellous bone in the metaphyseal area. Gain in diameter comes from subperiosteal new bone apposition by intramembranous bone formation. The periosteum is an envelope of fibrous connective tissue that is wrapped around diaphyses. The size of the marrow cavity is controlled by a combination of bone apposition and resorption at the endocortical surface. (B and C) In ICH/Caffey disease, hyperostosis develops by exacerbated subperiosteal intramembranous bone formation triggered by local inflammation (left side of B and C). In the remodeling phase, the excess of bone tissue is resorbed either at the endocortical surface, leading to an expansion of the marrow cavity and a more persistent deformity (right side of B), or at the exocortical surface, with no effect on the size of the marrow cavity (right side of C). local inflammation. Such a hypothesis collagen (6). The careful and elegant work the triple-helical domain. Because of its received strong support from a report by of Gensure et al. has established a strong small size, it packs tightly at the center of Ueda et al. (4) demonstrating that admin- linkage between the ICH phenotype and the helix and confers stability. A mutation istration of prostaglandin E (PGE) in the COL1A1 locus on chromosome 17q21 affecting a Gly residue will thus have an infants with ductus-dependent cyanotic in 3 discrete pedigrees from Australia and impact on the conformation of the colla- heart disease induced a form of cortical Canada with an autosomal dominant gen molecule, its integration in the tissue hyperostosis that mimics ICH. Two years form of ICH. More importantly, despite (bone, skin, and tendon), and the struc- later, Heyman et al. (5) reported that in 5 the fact that the families were geographi- tural qualities of the tissue. This is the affected children, PGE serum levels were cally dispersed and unrelated, it was case in osteogenesis imperfecta, or brittle significantly elevated and that treatment found that all affected individuals were bone disease, where most mutations with- with indomethacin (an inhibitor of PGE heterozygous for the identical mutation, in COL1A1 are glycine substitutions. The synthesis) rapidly suppressed irritabil- a substitution of Arg by Cys at position severity of the phenotype is determined ity and led to a progressive decrease in 836 (R836C), within the helical domain in part by the pattern of inheritance, the soft-tissue swelling in 6–9 days. Wheth- of the α1 chain of type I collagen. The position of the mutation in the α1 chain, er elevated PGE levels were a cause or a linkage and sequencing data are solid and and the bulkiness of the replacement resi- consequence of the lesions could not be convincing and represent a major step for- due, as it will variably compromise forma- answered. We have made the same obser- ward in the understanding of the pathol- tion and stability of the helix. vations in 3 patients (Glorieux et al., ogy of an elusive disease. In contrast, the R836C mutation iden- unpublished data). One has to now try and understand how tified by Gensure et al. (6) in these ICH a point mutation in a widely distributed patients would not be predicted to have ICH pathophysiology structural protein can initiate the cascade such an effect on the collagen molecule. At a time when the debate regarding of inflammatory events that lead to ICH. Why and how it would instead stimulate how a state of acute bone and soft-tissue Type I collagen, the most abundant pro- new bone formation through a process of inflammation could be limited in time tein present within bone, is also present inflammation has yet to be understood. and space and yet be transmitted as an in periosteum, ligaments, dermis, and There has been only one other Arg-to-Cys autosomal dominant trait with incom- tendon. It is made of a long, continuous substitution reported in the α1 chain of plete penetrance is at a virtual standstill triple helix that assembles in highly orga- type I human collagen. R134C is associ- comes the surprising finding reported in nized collagen fibrils. The fibrils have ated with classical Ehlers-Danlos syn- this issue of the JCI that ICH is closely high tensile strength, which is critical for drome (EDS), which is characterized by associated with a mutation in COL1A1, the function of bone and other tissues (7). skin hyperelasticity, joint hypermobility, the gene encoding the α1 chain of type I Glycine occurs at every third residue of increased tendency to bruise, and abnor-

The Journal of Clinical Investigation http://www.jci.org Volume 115 Number 5 May 2005 1143 commentaries mal scarring (8). Some of the clinical fea- the clinically observed reduced penetrance 1. Caffey, J., and Silverman, W. 1945. Infantile corti- tures of EDS are actually evident in the at the molecular level. Many unresolved cal hyperostosis, preliminary report of a new syndrome. American Journal of Rontgenology. 54:1–16. families with ICH studied by Gensure et questions regarding the pathology of this 2. Silverman, F.N. 1985. Infantile cortical hyperos- al. (6), and this makes sense. But the rea- disease may have to wait for the engineer- tosis. In Caffey’s pediatric x-ray diagnosis. F.N. Silver- son why some ICH patients also develop ing of an appropriate mouse model. man, editor. Year Book Medical Publishers. Chi- cago, Illinois, USA. 841–849. acute bone lesions at a specific age is In conclusion, by showing convincingly 3. Eversole, S.L., Holman, G.H., and Robinson, not clear. The authors hypothesize that that Caffey disease is associated with a R.A. 1957. Hitherto undescribed characteristics periosteum is only loosely attached to COL1A1 missense mutation, Gensure et of the pathology of infantile cortical hyperos- the underlying bone structure in infants al. (6) have once again demonstrated the tosis (Caffey’s disease). Bull. John Hopkins Hosp. 101:80–89. and that periosteum detachment (per- power of linkage analysis. They have lifted 4. Ueda, K., et al. 1980. Cortical hyperostosis follow- haps facilitated by the collagen muta- the lid of a black box, but what is inside the ing long-term administration of prostaglandin E1 tion) would be the primum movens lead- box remains to be discovered. in infants with cyanotic congenital heart disease. J. Pediatr. 97:834–836. ing to increased bone formation. Such a 5. Heyman, E., Laver, J., and Beer, S. 1982. Prostaglan- hypothesis is not entirely consistent with Acknowledgments din synthetase inhibitor in Caffey disease [letter]. the histologic studies done sequentially Work in the author’s laboratory is sup- J. Pediatr. 101:314. in cases of ICH (3), which clearly indicate ported by the Shriners of North America. 6. Gensure, R.C., et al. 2005. A novel COL1A1 mutation in infantile cortical hyperostosis (Caffey that inflammation is the initial event, The author wishes to thank Frank Rauch disease) expands the spectrum of collagen- in agreement with the clinical and PGE- for critical reading of the manuscript. related disorders. J. Clin. Invest. 115:1250–1257. related observations. It is noteworthy that doi:10.1172/JCI200522760. 7. Cole, W.G. 2003. Structure of growth plate and Gensure et al. found that 79% of the indi- Address correspondence to: Francis H. Glo- bone matrix. In Pediatric bone, biology and diseases. viduals studied who were heterozygous rieux, Genetics Unit, Shriners Hospital for F.H. Glorieux, J.M. Pettifor, and H. Jüppner, edi- for the COL1A1 mutation had an episode Children, 1529 Cedar Avenue, Montréal, tors. Academic Press. Oxford, United Kingdom/ of cortical hyperostosis, while 21% of the Quebec H3G 1A6, Canada. Phone: (514) Boston, Massachusetts, USA. 1–41. 8. Nuytinck, L., et al. 2000. Classical Ehlers-Danlos subjects carrying the R836C substitution 842-5964; Fax: (514) 843-5581; E-mail: syndrome caused by a mutation in type I collagen. do not develop disease, which confirms [email protected]. Am. J. Hum. Genet. 66:1398–1402. A tax on luxury: HTLV-I infection of CD4+CD25+ Tregs Robert S. Fujinami

Department of Neurology, University of Utah School of Medicine, Salt Lake City, Utah, USA.

Almost a quarter of a century ago, Oldstone and colleagues proposed sion molecules, and cytokines, appears to that infection of cells by noncytopathic viruses may lead to an alteration be one of the basic mechanisms underlying of the cells’ ability to produce certain products or perform certain tasks, the development of HTLV-I–associated dis- i.e., inhibition of “luxury function.” In this issue of the JCI, this topic has eases.” In this issue of the JCI, the study by been revisited by Yamano et al., who demonstrate that human T cell lym- Yamano et al. (2) provides an interesting con- photropic virus type I (HTLV-I) infection of CD4+CD25+ Tregs in patients firmation of Uchiyama’s précis. The authors with HTLV-I–associated myelopathy/tropical spastic paraparesis (HAM/ present data showing that the tax gene of TSP) results in a decrease in FOXP3 mRNA and protein expression (see HTLV-I can cause dysfunction of infected the related article beginning on page 1361). This leads to the inability of CD4+CD25+ Tregs and that the interaction HTLV-I–infected CD4+CD25+ Tregs to inhibit the proliferation of between these HTLV-I–infected Tregs and CD4+CD25− Tregs, due to the effect of the HTLV-I tax gene. Defects in other CD4+CD25− T cells is dysregulated. the Treg population could be responsible for the large numbers of virus- One could infer from the study by Oldstone specific T cells and occurrence of lymphoproliferation and inflammatory et al. (3) that viral infection of differentiated autoimmune disease in HAM/TSP patients. cells can lead to different outcomes, which depend on what type of cell is infected and Several years ago, Uchiyama (1) provided what gene product expression is turned off. interesting insight into the workings of HTLV-I is a human retrovirus that is Nonstandard abbreviations used: AC, asymptomatic HTLV-I–infected individual; HAM, HTLV-I–associated human T cell lymphotropic virus type I the etiologic agent for HTLV-I–associated myelopathy; HD, healthy donor; HTLV-I, human T (HTLV-I) infection. He stated that “The myelopathy/tropical spastic paraparesis cell lymphotropic virus type I; TSP, tropical spastic interaction between HTLV-I–infected cells (HAM/TSP). The prevalence of HAM is paraparesis. with dysregulated function and different about 2.4–3.8% in HTLV-I–positive indi- Conflict of interest: The author has declared that no conflict of interest exists. kinds of cells in the host, such as lympho- viduals (4, 5). Therefore, only a minority of Citation for this article: J. Clin. Invest. 115:1144–1146 cytes and vascular endothelial cells through infected individuals go on to develop HAM. (2005). doi:10.1172/JCI200525130. viral peptides, antigen receptors, cell adhe- Yamano et al. (2) explored HTLV-I infection

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